The Epidemiology Branch (DESPR) is conducting a number of studies in collaboration with the Health Research Board and Trinity College, Ireland. These investigations are designed to determine the biochemical mechanisms by which folate reduces the risk for neural tube defects. Data and blood samples have been collected on a large proportion of Irish women delivering babies in Dublin. Samples from women whose pregnancy ended in the delivery of a child with a neural tube defect and control women whose pregnancy ended in the delivery of a normal child are being studied. Samples are also being collected from families with an affected child. Various aspects of folate metabolism and other nutritional measures are being examined. We have demonstrated that at lower levels of B12, women carrying a fetus with an NTD have significantly higher levels of homocysteine than women carrying a normal fetus. We have also demonstrated that an abnormal gene responsible for elimination of homocysteine is involved. Specifically, a gene defect produces the so-called thermolabile variant of the 5,10 methylene tetrahydrofolate reductase enzyme. This abnormal enzyme is found significantly more frequently in individuals with NTDs than in normal individuals. We have expanded our investigation to include subjects with cleft lip and cleft palate. There are conflicting data on whether folic acid can prevent these oral clefts. We examined the relationship between clefts and the abnormal variant enzyme, thermolabile methylenetetrahydrofolate reductase (MTHFR). In the Irish population those with isolated cleft palates were significantly more likely to be homozygous (TT) for this enzyme. Thus, inability to convert folate to the methyl form may be an etiologic factor in oral clefts.